Abstract: Background: Interferon-β (IFN-β) is an immunomodulatory agent that has been approved in >80 countries worldwide for the treatment of multiple sclerosis (MS) with a relapsing course. Several studies have found IFN-β beneficial in reducing rates of relapse, whereas others have reported no benefit in this regard. Objective: A systematic review and meta-analysis of published placebo-controlled clinical trials of IFN-β was conducted to determine the efficacy and tolerability of IFN-β in the maintenance of remission of MS and to examine variations in effectiveness according to type of IFN-β and subtype of MS. Methods: PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (1966–May 2010) were searched for English-language reports of placebo- controlled trials on the efficacy and/or tolerability of IFN-β in MS. Three reviewers independently examined the abstracts of identified publications for relevance and extracted pertinent data from the selected reports. The key efficacy outcomes of interest were the number of patients with at least one relapse and the mean change in Expanded Disability Status Scale (EDSS) scores. The key tolerability outcomes were the number of discontinuations due to adverse events, number of deaths, and number of patients with completed suicides or suicide attempts. In addition, specific adverse events of interest (flulike symptoms, injection-site reactions, injection-site inflammation, myalgia, depression, leukopenia, lymphopenia, and increased alanine aminotransferase) were analyzed individually and compared between IFN-β and placebo. Results: Nine randomized, placebo-controlled clinical trials of IFN-β met the criteria for inclusion in the metaanalysis. These studies included a total of 3980 patients with MS (2639 with secondary progressive MS, 50 with primary progressive MS, 359 with relapsing MS, and 932 with relapsing-remitting MS; 2552 women, 1428 men; mean age, 40.6 years) randomized to receive either IFN-β or placebo. Of those randomized to treatment, 1893 received IFN-β-1a or placebo, 2029 received IFN-β-1b or placebo, and 58 received natural IFN-β or placebo. The summary relative risks (RRs) for at least one relapse compared with placebo were as follows: 0.86 (95% CI, 0.76 to 0.97; P = 0.011) for all types of IFN-β across all subtypes of MS (7 trials); 1.11 (95% CI, 0.79 to 1.55) for all types of IFN-β in secondary progressive MS (SPMS) (3 trials); and 0.77 (95% CI, 0.57 to 1.05) for all types of IFN-β in relapsing-remitting MS (2 trials). The summary RR for at least one relapse across all types of MS was 0.97 (95% CI, 0.57 to 1.67) for IFN-β-1a (3 trials) and 0.92 (95% CI, 0.85 to 1.00; P = 0.042) for IFN-β-1b (3 trials). The summary RR for at least one relapse was 0.93 (95% CI, 0.75 to 1.14) in patients with SPMS receiving IFN-β-1b. The pooled effect sizes for the mean change in EDSS score with the IFN-β doses used in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis Accepted for publication August 19, 2010. study were −1.71 (95% CI, −4.70 to 1.28) for the 22-μg dose and −1.71 (95% CI, −4.70 to 1.27) for the 44-μg dose (2 trials). For the tolerability outcomes, the summary RRs were 2.76 (95% CI, 1.97 to 3.89; P < 0.001) for discontinuation due to adverse events (9 trials), 1.53 (95% CI, 0.45 to 5.15) for death (3 trials), and 0.86 (95% CI, 0.41 to 1.79) for completed suicides and suicide attempts (5 trials). The summary RRs for all adverse events of interest (with the exception of depression) were statistically significant for all types of IFN-β compared with placebo across all types of MS (P < 0.01). Conclusions: In this meta-analysis of 9 randomized clinical trials, IFN-β was associated with prevention of relapse compared with placebo across all subtypes of MS. However, the effectiveness of IFN-β appeared to vary depending on the type of IFN-β used and the subtype of MS treated. [Copyright &y& Elsevier]